The present invention relates to novel tricyclic compounds which strongly antagonize a biological action of thromboxane A2 (hereafter referred to as "TXA.sub.2 ") by an inhibitory activity of TXA.sub.2 biosynthesis and/or a TXA.sub.2 receptor antagonizing activity.
It is hitherto known that TXA.sub.2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidoic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. Further TXA.sub.2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA.sub.2 is considered to take part in pathological conditions over a wide range. As examples, the following diseases can be exemplified.
(1) Ischemic disease
For example, myocardial infarction, angina pectoris, and thrombosis
(2) Cerebro-vascular disease
For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction
(3) Peripheral vascular diseases and disease caused by unbalanced lipid
For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, pulmonary embolism
(4) Inflammatory and allergic diseases
For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
(5) Shock
(6) Cancer metastasis.
Accordingly, compounds that antagonize the action of TXA.sub.2 (compounds having an inhibitory action of TXA.sub.2 biosynthesis and/or a TXA.sub.2 receptor antagonizing action) are expected to have therapeutic effects in preventing or treating optional one or more of the diseases described above or other diseases in which the action of TXA.sub.2 is desirably prevented. Further where, in drugs used for medical purposes heretofore, application thereof is limited due to side effects mediated by TXA.sub.2 or considered to be mediated by TXA.sub.2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA.sub.2.
As inhibitors against biosynthesis of TXA.sub.2, representative compounds are exemplified in Journal of Organic Synthesis Chemistry, 45, 2 (1987). In addition, compounds having the following structures can be illustrated. ##STR2##
The compounds contain a pyridine or imidazole partial structure and carboxyl therein and it is known that these functional groups are important for developing the action.
On the other hand, as an antagonist or TXA.sub.2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986).
Furthermore, an indole compound having the following structure: ##STR3## and the like are disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR4## and the like are disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [DE 3,508,692]. These compounds are all derivatives having a phenylsulfonamide group and exhibit an activity of antagonizing TXA.sub.2.
Furthermore, there is reported a finding on the enhanced or complementary effect of the two activities by the use of TXA.sub.2 biosynthesis inhibitors and TXA.sub.2 receptor antagonists in combination [Eur. J. Pharmacol., 85, 331 (1982)].
There is also a report on compounds having both TXA.sub.2 biosynthesis inhibitory action and TXA.sub.2 receptor antagonizing action [Thromb. Haemostasis, 58, 664 (1987), etc.].
In tricyclic compounds in association with the present invention which are represented by the following formula (II): ##STR5## oxepine derivatives (wherein X.sup.A --X.sup.B is --CH.sub.2 O--) having carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as a carboxylic acid group) as a substituent (X.sup.C) on the benzene ring wherein the 11-position (X.sup.D) is unsubstituted or has various substituents such as oxo (.dbd.O), methylene (.dbd.CH.sub.2), alkoxy, etc. are known as showing antiinflammatory and antiallergic activities, and the like [J. Med. Chem., 19, 941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No. 4,282,365 (Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788, Japanese Published Unexamined Patent Application Nos. 152673/1986, 152674/1986 and 152675/1986].
There are also known oxepine derivatives showing antiasthmic and antiallergic activities, etc. wherein X.sup.C is unsubstituted or has a substituent other than the carboxylic acid group, for example, alkyl, alkoxy, halogen, etc. and X.sup.D has an alkylene chain substituted at the terminal thereof with alkylamino via hetero atom (--NH--, --O--, --S--, etc.), methine (=CH--), imino (=N--), etc. [Japanese Published Unexamined Patent Application Nos. 126883/1983 (EP 0085870A), 227879/1984 and 152669/1986; U.S. Pat. Nos. 3,354,155 and 3,420,851]. Furthermore, oxepine derivatives wherein X.sup.D contains phenyl or, an alicyclic or aromatic uheterocyclic group at the terminal thereof via --NH-- are known to show anticholinergic and antihistaminic activities, etc. [Japanese Published Unexamined Patent Application Nos. 150083/1981 (U.S. Pat. Nos. 4,396,550 and 4,465,835), and 139073/1982]. As the heterocyclic rings, piperazine, piperidine, morpholine, pyrrolidine, quinuclidine, pyridine, benzodioxane, indole and quinone are illustrated. Furthermore, cycloheptene derivatives --X.sup.B is --CH.dbd.CH--) or thiepine derivatives --X.sup.b is -- CH.sub.2 S--) wherein X.sup.D contains at the terminal thereof an alicyclic saturated nitrogen-containing heterocyclic group, for example, piperazine, via --CONH-- are known to show a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (U.S. Pat. No. 4,749,703) and 153280/1987]. Furthermore, doxepin derivatives [X.sup.A --X.sup.B is --CH.sub.2 O--; Drugs, 13, 161 (1977)]or dothiepin derivatives X.sup.A --X.sup.B is --CH.sub.2 S--; Arz.-Forsch., 13, 1039 (1963), ibid., 14, 100 (1964)]wherein X.sup.C is hydrogen and X.sup.D has dimethylaminoisopropylidene as its substituent are known to show an antidepressive action.
Furthermore, oxepine derivatives having an antiallergic activity wherein X.sup.C has the carboxylic acid group and X.sup.D has an alkylene chain substituted at the terminal thereof with alkylamino via a hetero atom, or its 11-position is directly bound to an alicyclic saturated heterocyclic ring such as piperazine or homopiperazine, etc. are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804), 152670/1986, 152671/1986, 152672/1986, 152676/1986, 257981/1986 and 17877/1988]. Likewise, there are known compounds having an imidazole ring directly bound to its 11-position [Japanese Published Unexamined Patent Application No. 21679/1983 (U.S. Pat. No. 4,282,365)]. There are also disclosed oxepine or cycloheptene --X.sup.B is --CH.sub.2 CH.sub.2 --] derivatives showing an antihistaminic activity wherein X.sup.D is alkylaminoalkylidene [Japanese Published Unexamined Patent Application No. 45557/1987 (British Patent No. 8,520,662)]. Furthermore, there are disclosed oxepine derivatives showing antiallergic and antiinflammatory activities, etc. wherein contains at the terminal thereof alkylamino or alicyclic saturated nitrogen-containing heterocyclic group via methine, methylene or. imino (Japanese Published Unexamined Patent Application No. 10784/1988). As the heterocyclic groups, 4-methylpiperazine, 4-methylhomopiperazine, piperidine, pyrrolidine, thiomorpholine and morpholine are exemplified.
Novel and useful TXA.sub.2 antagonists (drugs having the TXA.sub.2 biosynthesis inhibitory activity and/or TXA.sub.2 receptor antagonizing activity) are expected to have preventive and therapeutic effects on various diseases, and are in demand.